γ-halo-enones: A method for their synthesis from arylacyl halides and their application to the preparation of five-membered ring heterocycles

Article abstract of DOI:10.1021/jo5001274

A simple method has been developed for synthesis of γ-halo-enones. The approach employs a sequence involving initial indium-mediated allenylation reactions of phenacyl halides with propargyl bromide. This process is followed by acid-promoted rearrangement reactions of the formed homoallenic halohydrins. The new method can be incorporated into routes for the efficient synthesis of various five-membered heterocyclic compounds.

Full text of DOI:10.1021/jo5001274

Note
pubs.acs.org/joc
γ‑Halo-enones: A Method for their Synthesis from Arylacyl Halides
and Their Application to the Preparation of Five-Membered Ring
Heterocycles
Mei-Huey Lin,* Yen-Chih Huang, Chung-Kai Kuo, Chang-Hsien Tsai, Yi-Syuan Li, Ting-Chia Hu,
and Tsung-Hsun Chuang
Department of Chemistry, National Changhua University of Education, Changhua, Taiwan 50007
S
* Supporting Information
ABSTRACT: A simple method has been developed for
synthesis of γ-halo-enones. The approach employs a sequence
involving initial indium-mediated allenylation reactions of
phenacyl halides with propargyl bromide. This process is
followed by acid-promoted rearrangement reactions of the
formed homoallenic halohydrins. The new method can be
incorporated into routes for the efficient synthesis of various five-membered heterocyclic compounds.
ecently, gold- and other metal-promoted nucleophilic
cyclization reactions of functionalized allenes have become
The feasibility of the new approach to the preparation of γ-
halo-enones 1 is critically dependent on the availability of a
method for the efficient synthesis of homoallenic halohydrins 4.
Although an earlier procedure to access these targets, utilizing
selective allenylation reactions of allenylboronate pinacol esters
with α-bromoacetophenone, has been described,4,5 the cost and
tediousness of the required operations make it nonideal for
most applications. We envisaged that a simple approach to the
synthesis of homoallenic halohydrin would involve selective
allenylation reactions of arylacyl halides 5 with propargyl
bromide.
Previously, we reported that homoallylic bromohydrins are
generated in indium-mediated allylation reactions of α-
bromoketones in water.6 To explore the applicability of this
strategy, indium-mediated allenylation reactions of arylacyl
halides with propargyl bromide in aqueous media were
investigated. These reactions were found to produce the
desired allenic halohydrins in good yields along with small
amounts of both the propargyl analogues and corresponding
methylketones, formed by direct reduction of the arylacyl
halides (Table 1). Importantly, the allenylation versus
propargylation product ratios are at least 3:1. Unfortunately,
chromatographic purifications of the desired homoallenic
halohydrins are difficult in most cases because the allene
products and methyl ketones have overlapping chromato-
graphic mobilities. In fact, only homoallenic bromohydrin
4c,h,i can be isolated as a pure substance by using a meticulous
chromatographic procedure. While the analogues 4a,b and 4d−
g can be isolated in pure form by first treating the crude
reaction mixtures with sodium borohydride followed by
chromatography, in these cases partial reductive removal of
bromine from the homoallenic bromohydrins takes place. As a
R
powerful methods to prepare various five-membered hetero-
cyclic substances.1 Although γ-halo-enones 1, which have a
functionally intriguing skeleton, are useful intermediates in the
synthesis of a variety of heterocycles, such as furans, pyrroles,
and thiophenes,2 their preparation and properties have not yet
been fully explored. In fact, in this family only (Z)-1,3-bis(aryl)-
4-bromo-2-buten-1-ones have been studied. Inspiration for the
current study came from both a recognition of this deficiency
and earlier observations that demonstrated that 1-aryl-3-halo-
1,3-dienes 3 can be prepared through SN2′-type addition−
elimination reactions of 1-aryl-2,3-allenols 2 with lithium
halides in acetic acid (Scheme 1).3 In this effort we have
successfully explored a new strategy for the preparation of γ-
halo-enones 1 that is based on a proposed rearrangement
reaction of homoallenic halohydrin 4.
Scheme 1
Received: January 19, 2014
Published: March 5, 2014
© 2014 American Chemical Society
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Note
a
worth noting that the yield of the process is the same
independent of whether a crude mixture containing homo-
allenic bromohydrin 4c and acetophenone 4c″ or a
meticulously purified sample of 4c is used as the starting
material. Finally, we observed that the γ-halo-enones 1 readily
decompose at room temperature and even slowly degrade when
stored in a freezer. The stability of these substances is affected
by the nature and position of substituents as exemplified by the
observation that 1h is less stable than 1i and that 1a−e are
relatively more stable.
Table 1. Indium-Mediated Allenylation and γ-Halo-enone-
b
Forming Acid-Promoted Rearrangement Reactions
An effort was conducted to explore applications of the γ-
bromo-enones 1 as intermediates in the synthesis of a variety of
five-membered heterocyclic compounds. As demonstrated by
the processes displayed in Schemes 2, 3, and 4, the γ-bromo-
Scheme 2. Formation of 1,2,4-Substituted Pyrroles
Scheme 3. Formation of 2,4-Substituted Thiophenes
a
Condition: 5 (1.0 mmol), propargyl bromide (133.8 μL, 1.8 mmol),
and indium (99.99%, 325 mesh, 172.2 mg, 1.5 mmol) in THF (1.5
b
mL)/water (0.5 mL) at rt. Condition: 4 (0.8 mmol) and H2SO4
c
(0.05 mL) in CH2Cl2 (5 mL) at rt for 2 h. Ratio was determined by
d
1H NMR. Overall yield from 5.
consequence of this issue, crude product mixtures containing
the homoallenic halohydrins 4 and methyl ketone 4″ were
directly employed in the following γ-halo-enone forming
reactions. It is necessary to remove the propargylation product
4′ from the crude product mixture because 4′ and 1 have
overlapping chromatographic mobilities.
It is known that acid-catalyzed Nazarov-type cyclization
reactions of terminally disubstituted tertiary α-allenic alcohols
take place to generate benzofulvenes7 and that these processes
occur more slowly when terminally monosubstituted allenes are
employed as substrates. This observation suggests that
terminally nonsubstituted homoallenic halohydrins 4 might
react under acid-promoted conditions by a hydroxyl rearrange-
ment-type pathway to produce the corresponding γ-halo-
enones. An exploration using bromohydrin 4e and a variety of
acid catalysts demonstrated the γ-bromo-enone 1e generating
reaction does indeed take place in moderately high efficiency,
especially when sulfuric acid is employed as the promoter. It is
Scheme 4. Formation of 2,4-Substituted Furans
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UV and a solution of phosphomolybdic acid in ethanol (5 wt %) or p-
enones 1 can be employed as starting materials for reactions
that generate pyrroles, thiophenes, and furans. Interestingly, the
furan-forming reactions take place through the intermediacy of
γ-hydroxy-enones, which then undergo ready dehydration and
tandem cycloaromatization when treated with mild base to
form furans.8 The success of the heterocyclic ring-forming
reactions suggests that the acid-promoted rearrangement
reactions of homoallenic bromohydrins give (Z)-γ-bromo-
enones 1. This stereochemical proposal was confirmed by
performing X-ray crystallographic analysis on 1b and 1g.9
Finally, owing to the intrinsic instability of γ-bromo-enones 1
(see above), a concise procedure was developed for the three-
step synthesis of thiophenes from arylacyl bromides, in which
only the ultimate heterocyclic products were subjected to
purification (Table 2). Using this approach, it was possible to
anisaldehyde stain. Flash chromatography was performed using silica
1
gel (70−230 mesh). H NMR spectra were recorded on a 300 MHz
spectrometer. 13C NMR spectra were recorded on a 75 MHz
spectrometer with complete proton decoupling. Chemical shifts are
reported relative to CHCl3 [δH 7.24, δC (central line) 77.0]. Mass
spectra were recorded under electron spray interface (ESI) conditions,
and high-resolution mass spectra were recorded by electron impact
ionization with magnetic sector or orbitrap analyzer.
General Procedure for Indium-Mediated Allenylation Re-
actions of Arylacyl Halide 5 with Propargyl Bromide. A mixture
of propargyl bromide (133.8 μL, 1.8 mmol), indium powder (325
mesh, 172.2 mg, 1.5 mmol), and arylacyl halide 5 (1.0 mmol) in THF/
H2O (1.5 mL/0.5 mL) was stirred at ambient temperature. The
reaction was monitored by TLC until no starting material was
observed, and normally the reaction was stirred at rt overnight. Et2O
(10 mL) and water (10 mL) were then added to the reaction, and the
mixture was transferred to a separatory funnel. The aqueous layer was
back extracted with Et2O (5 mL × 2). The combined organic layers
were washed with brine (3 mL), dried over MgSO4, and concentrated
in a rotary evaporator. The residue was purified by silica gel
chromatography using hexanes to Et2O/hexanes (1:20) as eluent to
give the product 4 and the corresponding methyl ketone 4″, which
were used for the next step directly. Pure compounds 4c, 4h, and 4i
were purified by using hexanes to Et2O/hexanes (1:100) as eluent.
General Procedure for Acid-Promoted Rearrangement
Reactions of Homoallenic Bromohydrins 4. To a solution of
homoallenic bromohydrin 4 (0.8 mmol) in CH2Cl2 (5 mL) was added
concentrated sulfuric acid (0.05 mL). The resulting mixture was stirred
at ambient temperature. The reaction was monitored by TLC until no
starting material was observed, and normally the reaction was stirred at
rt for 2 h. Water (10 mL) and CH2Cl2 (10 mL) were then added to
the reaction, and the mixture was transferred to a separatory funnel.
The aqueous layer was back extracted with CH2Cl2 (10 mL × 2). The
combined organic layers were washed with brine (5 mL), dried over
MgSO4, and concentrated in a rotary evaporator. The residue was
purified by silica gel chromatography using hexanes to Et2O/hexanes
(1:100) as eluent to give the product 1. For compound 1g, Et2O/
hexanes (1:100) to Et2O/hexanes (1:15) was used as eluent.
Table 2. Preparation of Substituted Thiophenes from
Phenacyl Bromides
General Procedure for the Formation of Thiophenes 7 from
Phenacyl Bromides in the 3-Step Sequence. A mixture of
propargyl bromide (1.8 mmol, 133.8 μL), indium powder (325 mesh,
172.2 mg, 1.5 mmol), and arylacyl halide (5, 1.0 mmol) in THF/H2O
(1.5 mL/0.5 mL) was stirred at ambient temperature. The reaction
was monitored by TLC until no starting material was observed, and
normally the reaction was stirred at rt overnight. Et2O (10 mL) and
water (5 mL) were then added to the reaction, and the mixture was
transferred to a separatory funnel. The aqueous layer was back
extracted with Et2O (5 mL × 2). The combined organic layers were
washed with brine (3 mL), dried over MgSO4, and concentrated in a
rotary evaporator. The residue was dissolved in CH2Cl2 (5 mL), and
then concentrated sulfuric acid (0.05 mL) was added. The resulting
mixture was stirred at ambient temperature for 2 h. Water (10 mL)
and CH2Cl2 (10 mL) were then added to the reaction, and the mixture
was transferred to a separatory funnel. The aqueous layer was back
extracted with CH2Cl2 (10 mL × 2). The combined organic layers
were washed with brine (5 mL), dried over MgSO4, and concentrated
in a rotary evaporator. The residue was dissolved in EtOH (2 mL), and
then thioacetamide (1.0 mmol, 75.1 mg) was added. The resulting
mixture was heated to reflux for 1 h, cooled to rt, and concentrated in a
rotary evaporator. The mixture was diluted with CH2Cl2 (10 mL) and
washed with water (5 mL). The aqueous layer was back extracted with
CH2Cl2 (10 mL × 2). The combined organic layers were washed with
brine (5 mL), dried over MgSO4, and concentrated in a rotary
evaporator. The residue was purified by silica gel chromatography
using hexanes to EtOAc/hexanes (1:8) as eluent to give the product 7.
General Procedure for the Formation of 1,2,4-Substituted-
pyrroles 6a−g from γ-Bromo-enones 1c−e. A mixture of γ-
bromo-enones 1 (0.6 mmol) and aniline (1.2 mmol, 109.6 μL) in
methanol (2.0 mL) was heated to reflux overnight. The mixture was
prepare substituted thiophenes from readily available arylacyl
bromides in good overall yields even in those cases where the
intermediate γ-bromo-enones are highly unstable (1j, 1k) or
difficult to purify (1l).
In conclusion, the studies described above have led to the
development of a new and simple method for the preparation
of 5-halo-4-aryl-pent-3-en-2-ones 1 from arylacyl halides and
applications of these substances to the synthesis of substituted
pyrroles, thiophenes, and furans.
EXPERIMENTAL SECTION
General Information and Materials. All commercially available
chemicals were used without further purification. TLC analyses were
run on a TLC glass plate (Silica gel 60 F254) and were visualized using
■
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Note
cooled to rt and concentrated in a rotary evaporator. CH2Cl2 (10 mL)
and water (10 mL) were added to the residue, and the mixture was
transferred to a separatory funnel. The aqueous layer was back
extracted with CH2Cl2 (10 mL × 2). The combined organic layers
were washed with brine (5 mL), dried over MgSO4, and concentrated
in a rotary evaporator. The residue was purified by silica gel
chromatography using hexanes to Et2O/hexanes (1:100) as eluent
to give the product 6.
127.9 (CH × 2), 128.8 (CH × 2), 135.7 (C), 136.8 (C), 149.5 (C),
197.8 (C); IR (neat) 3029, 1690, 1611 cm−1; EI-MS m/z (rel
intensity) 274 ([M + 2]+, 46), 272 ([M]+, 35), 257 (28), 193 (100);
HRMS [M]+ calcd for C11H10BrClO 271.9604, found 271.9614.
(Z)-5-Bromo-4-(4-bromophenyl)pent-3-en-2-one (1e, Table
1, entry 5). Following the general procedure, the title compound was
obtained (178 mg, 56% from 5e). An oil; TLC (Et2O/hexanes (1:5))
Rf = 0.33; 1H NMR (300 MHz, CDCl3) δ 2.32 (s, 3 H), 4.82 (s, 2 H),
6.49 (s, 1 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.51 (d, J = 8.0 Hz, 2 H); 13C
NMR (75 MHz, CDCl3) δ 26.3 (CH2), 32.3 (CH3), 124.1 (C), 125.9
(CH), 128.2 (CH × 2), 131.9 (CH × 2), 137.3 (C), 149.7 (C), 197.8
(C); IR (neat) 3076, 1692, 1595 cm−1; EI-MS m/z (rel intensity) 318
([M + 2]+, 23), 316 ([M]+, 14), 237 (33), 158 (100); HRMS [M]+
calcd for C11H10Br2O 315.9098, found 315.9109.
General Procedure for the Formation of 2,4-Substituted-
thiophenes 7c−e from γ-Bromo-enones 1c−e. A mixture of γ-
bromo-enones 1 (0.6 mmol) and thioacetamide (0.6 mmol, 45.1 mg)
in ethanol (2.0 mL) was heated to reflux for 1 h. The mixture was
cooled to rt and concentrated in a rotary evaporator. CH2Cl2 (10 mL)
and water (5 mL) were added to the residue, and the mixture was
transferred to a separatory funnel. The aqueous layer was back
extracted with CH2Cl2 (10 mL × 2). The combined organic layers
were washed with brine (5 mL), dried over MgSO4, and concentrated
in a rotary evaporator. The residue was purified by silica gel
chromatography using hexanes as eluent to give the product 7.
General Procedure for the Formation of 2,4-Substituted-
furans 8c−e from γ-Bromo-enones 1c−e. A mixture of γ-bromo-
enones 1 (0.6 mmol) and NaOAc (1.2 mmol, 91.9 mg) in methanol
(2.0 mL) was heated to reflux for 5 h. The mixture was cooled to rt,
and then anhydrous K2CO3 (1.2 mmol, 165.8 mg) was added. The
resulting mixture was stirred at rt overnight and then filtered. The
filtrate was concentrated in a rotary evaporator. CH2Cl2 (10 mL) and
water (5 mL) were added to the residue, and the mixture was
transferred to a separatory funnel. The aqueous layer was back
extracted with CH2Cl2 (10 mL × 2). The combined organic layers
were washed with brine (5 mL), dried over MgSO4, and concentrated
in a rotary evaporator. The residue was purified by silica gel
chromatography using hexanes as eluent to give the product 8.
(Z)-5-Chloro-4-phenylpent-3-en-2-one (1a, Table 1, entry 1).
Following the general procedure, the title compound was obtained (88
(Z)-5-Bromo-4-(p-tolyl)pent-3-en-2-one (1f, Table 1, entry
6). Following the general procedure, the title compound was obtained
(104 mg, 41% from 5f). An oil; TLC (Et2O/hexanes (1:5)) Rf =
1
0.33;); H NMR (300 MHz, CDCl3) δ 2.32 (s, 3 H), 2.37 (s, 3 H),
4.88 (s, 2 H), 6.52 (s, 1 H), 7.20 (d, J = 8.4 Hz, 2 H), 7.44 (d, J = 8.4
Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 21.3 (CH3), 26.7 (CH2),
32.4 (CH3), 124.9 (CH), 126.6 (CH × 2), 129.5 (CH × 2), 135.5
(C), 140.2 (C), 151.1 (C), 198.1 (C); IR (neat) 3022, 1687, 1599
cm−1; EI-MS m/z (rel intensity) 254 ([M + 2]+, 9), 252 ([M]+, 10),
237 (16), 173 (100); HRMS [M]+ calcd for C12H13BrO 252.0150,
found 252.0146.
(Z)-4-(1-Bromo-4-oxopent-2-en-2-yl)benzonitrile (1g, Table
1, entry 7). Following the general procedure, the title compound was
obtained (132 mg, 50% from 5g). Solid, mp 73−74 °C; TLC (Et2O/
1
hexanes (1:5)) Rf = 0.33; H NMR (300 MHz, CDCl3) δ 2.33 (s, 3
H), 4.81 (s, 2 H), 6.51 (s, 1 H), 7.61 (d, J = 8.7 Hz, 2 H), 7.68 (d, J =
8.7 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 26.0 (CH2), 32.3 (CH3),
113.3 (C), 118.1 (C), 127.4 (CH × 2), 127.7 (CH), 132.4 (CH × 2),
143.1 (C), 148.8 (C), 197.7 (C); IR (KBr) 2216, 1690, 1597 cm−1; EI-
MS m/z (rel intensity) 265 ([M + 2]+, 41), 263 ([M]+, 42), 184 (82),
140 (100); HRMS [M]+ calcd for C12H10BrNO 262.9946, found
262.9949.
(Z)-5-Bromo-4-(4-methoxyphenyl)pent-3-en-2-one (1h,
Table 1, entry 8). Following the general procedure, the title
compound was obtained (112 mg, 52%). An oil; TLC (Et2O/hexanes
(1:5)) Rf = 0.33; 1H NMR (300 MHz, CDCl3) δ 2.31 (s, 3 H), 3.82 (s,
3 H), 4.89 (s, 2 H), 6.51 (s, 1 H), 6.92 (d, J = 9.0 Hz, 2 H), 7.53 (d, J
= 9.0 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 26.6 (CH2), 32.4
(CH3), 55.3 (CH3), 114.2 (CH × 2), 123.8 (CH), 128.1 (CH × 2),
130.4 (C), 150.5 (C), 161.0 (C), 198.0 (C); IR (KBr) 2947, 1671,
1578 cm−1; EI-MS m/z (rel intensity) 270 ([M + 2]+, 18), 268 ([M]+,
18), 189 (100), 130 (43); HRMS [M]+ calcd for C12H13BrO2
268.0099, found 268.0092.
(Z)-5-Bromo-4-(2-methoxyphenyl)pent-3-en-2-one (1i,
Table 1, entry 9). Following the general procedure, the title
compound was obtained (121 mg, 56%). An oil; TLC (Et2O/hexanes
(1:5)) Rf = 0.33; 1H NMR (300 MHz, CDCl3) δ 2.28 (s, 3 H), 3.81 (s,
3 H), 4.91 (s, 2 H), 6.25 (s, 1 H), 6.80−6.96 (m, 2 H), 7.18 (d, J = 8.0
Hz, 1 H), 7.35 (m, 1 H); 13C NMR (75 MHz, CDCl3) δ 29.0 (CH2),
32.1 (CH3), 55.4 (CH3), 110.7 (CH), 120.6 (CH), 128.2 (CH), 128.5
(C), 130.3 (CH), 130.5 (CH), 152.1 (C), 156.4 (C), 198.2 (C); IR
(neat) 3075, 1635, 1355 cm−1; EI-MS m/z (rel intensity) 270 ([M +
2]+, 5), 268 ([M]+, 5), 239 (100), 189 (50); HRMS [M]+ calcd for
C12H13BrO2 268.0099, found 268.0096.
1-Chloro-2-phenylpenta-3,4-dien-2-ol (4a, Table 1, entry 1).
Following the general procedure, a mixture of 4a and its corresponding
methyl ketone 4a″ was obtained. To the mixture in MeOH (2 mL)
was added NaBH4 (25 mg, 0.65 mmol) at rt, and the resulting mixture
was stirred at rt for 2 h. Et2O (15 mL) and water (3 mL) were added,
and the mixture was transferred to a separatory funnel. The aqueous
layer was back extracted with Et2O (15 mL × 2). The combined
organic layers were concentrated in a rotary evaporator. The residue
was purified by silica gel chromatography using hexanes to Et2O/
hexanes (1:100) as eluent to give the product 4a (94 mg, 48%). An oil;
TLC (Et2O/hexanes (1:5)) Rf = 0.35; 1H NMR (300 MHz, CDCl3) δ
2.93 (s, 1 H), 3.81 (d, J = 11.1 Hz, 1 H), 3.89 (d, J = 11.1 Hz, 1 H),
1
mg, 45% from 5a). An oil; TLC (Et2O/hexanes (1:5)) Rf = 0.38; H
NMR (300 MHz, CDCl3) δ 2.33 (s, 3 H), 4.98 (s, 2 H), 6.55 (s, 1 H),
7.39−7.42 (m, 3 H), 7.51−7.55 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ 32.2 (CH3), 39.2 (CH2), 126.5 (CH), 126.7 (CH × 2),
128.7 (CH × 2), 129.7 (CH), 138.2 (C), 150.4 (C), 198.1 (C); IR
(neat) 3022, 1669, 1599 cm−1; EI-MS m/z (rel intensity) 196 ([M +
2]+, 22), 194 ([M]+, 74), 158 (37), 115 (100); HRMS [M]+ calcd for
C11H11ClO 194.0498, found 194.0493.
(Z)-5-Chloro-4-(2,4-dichlorophenyl)pent-3-en-2-one (1b,
Table 1, entry 2). Following the general procedure, the title
compound was obtained (138 mg, 52% from 5b). Solid, mp 64−65
°C; TLC (Et2O/hexanes (1:5)) Rf = 0.30; 1H NMR (300 MHz,
CDCl3) δ 2.30 (s, 3 H), 4.89 (s, 2 H), 6.23 (s, 1 H), 7.19 (d, J = 8.1
Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 1.8 Hz, 1 H); 13C
NMR (75 MHz, CDCl3) δ 32.0 (CH3), 40.9 (CH2), 127.1 (CH),
129.6 (CH), 130.1 (CH), 131.5 (CH), 132.7 (C), 135.1 (C), 136.5
(C), 149.1 (C), 197.9 (C); IR (KBr) 2956, 1708, 1606 cm−1; EI-MS
m/z (rel intensity) 264 ([M + 2]+, 19), 262 ([M]+, 20), 227 (100),
183 (29); HRMS [M]+ calcd for C11H9Cl3O 261.9719, found
261.9726.
(Z)-5-Bromo-4-phenylpent-3-en-2-one (1c, Table 1, entry 3).
Following the general procedure, the title compound was obtained
1
(130 mg, 68%). An oil; TLC (Et2O/hexanes (1:5)) Rf = 0.33; H
NMR (300 MHz, CDCl3) δ 2.30 (s, 3 H), 4.87 (s, 2 H), 6.51 (s, 1 H),
7.30−7.41 (m, 3 H), 7.50−7.55 (m, 2 H); 13C NMR (75 MHz,
CDCl3) δ 26.7 (CH2), 32.2 (CH3), 125.6 (CH), 126.5 (CH × 2),
128.6 (CH × 2), 129.6 (CH), 138.3 (C), 150.8 (C), 197.9 (C); IR
(neat) 3059, 1682, 1353 cm−1; EI-MS m/z (rel intensity) 240 ([M +
2]+, 26), 238 ([M]+, 27), 223 (11), 159 (100); HRMS [M]+ calcd for
C11H11BrO 237.9993, found 237.9983.
(Z)-5-Bromo-4-(4-chlorophenyl)pent-3-en-2-one (1d, Table
1, entry 4). Following the general procedure, the title compound was
obtained (137 mg, 50% from 5d). An oil; TLC (Et2O/hexanes (1:5))
Rf = 0.30; 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3 H), 4.84 (s, 2 H),
6.49 (s, 1 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.47 (d, J = 8.0 Hz, 2 H); 13C
NMR (75 MHz, CDCl3) δ 26.4 (CH2), 32.3 (CH3), 125.8 (CH),
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5.02 (d, J = 6.6 Hz, 2 H), 5.55 (t, J = 6.6 Hz, 1 H), 7.27−7.39 (m, 3
H), 7.50 (d, J = 8.7 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 53.7
(CH2), 74.5 (C), 79.7 (CH2), 96.3 (CH), 125.5 (CH × 2), 127.8
(CH), 128.3 (CH × 2), 142.2 (C), 206.7 (C); IR (neat) 3538, 3067,
1967 cm−1; ESI-MS m/z (rel intensity) 219 ([M + Na + 2]+, 21), 217
([M + Na]+, 58), 197 (37), 55 (100); HRMS [M + Na]+ calcd for
C11H11OClNa 217.0391, found 217.0383.
δ 43.8 (CH2), 73.6 (C), 80.2 (CH2), 96.3 (CH), 121.9 (C), 127.3
(CH × 2), 131.4 (CH × 2), 141.3 (C), 206.6 (C); IR (neat) 3548,
1958, 1514 cm−1; ESI-MS m/z (rel intensity) 321 ([M + H + 4]+, 50),
319 ([M + H + 2]+, 100), 317 ([M + H]+, 55) 305 (8); HRMS [M +
H]+ calcd for C11H11OBr2 316.9171, found 316.9187.
1-Bromo-2-(p-tolyl)penta-3,4-dien-2-ol (4f, Table 1, entry 6).
Following the general procedure, a mixture of 4f and its corresponding
methyl ketone 4f″ was obtained. To the mixture in MeOH (2 mL) was
added NaBH4 (25 mg, 0.65 mmol) at rt, and the resulting mixture was
stirred at rt for 2 h. Et2O (15 mL) and water (3 mL) were added, and
the mixture was transferred to a separatory funnel. The aqueous layer
was back extracted with Et2O (15 mL × 2). The combined organic
layers were concentrated in a rotary evaporator. The residue was
purified by silica gel chromatography using hexanes to Et2O/hexanes
(1:100) as eluent to give the product 4f (104 mg, 41%). An oil; TLC
(Et2O/hexanes (1:5)) Rf = 0.40; 1H NMR (300 MHz, CDCl3) δ 2.33
(s, 3 H), 2.84 (s, 1 H), 3.72 (d, J = 10.5 Hz, 1 H), 3.79 (d, J = 10.5 Hz,
1 H), 5.02 (d, J = 6.6 Hz, 2 H), 5.54 (t, J = 6.6 Hz, 1 H), 7.17 (d, J =
8.1 Hz, 2 H), 7.37 (d, J = 8.1 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ
21.0 (CH3), 44.5 (CH2), 73.6 (C), 79.9 (CH2), 96.8 (CH), 125.3 (CH
× 2), 128.9 (CH × 2), 137.6 (C), 139.3 (C), 206.5 (C); IR (neat)
3548, 1948, 1477 cm−1; ESI-MS m/z (rel intensity) 255 ([M + H +
2]+, 37), 253 ([M + H]+, 34), 197 (51), 175 (100); HRMS [M + H]+
calcd for C12H14OBr 253.0223, found 253.0213.
1-Chloro-2-(2,4-dichlorophenyl)penta-3,4-dien-2-ol (4b,
Table 1, entry 2). Following the general procedure, a mixture of
4b and its corresponding methyl ketone 4b″ was obtained. To the
mixture in MeOH (2 mL) was added NaBH4 (25 mg, 0.65 mmol) at
rt, and the resulting mixture was stirred at rt for 2 h. Et2O (15 mL) and
water (3 mL) were added and the mixture was transferred to a
separatory funnel. The aqueous layer was back extracted with Et2O (15
mL × 2). The combined organic layers were concentrated in a rotary
evaporator. The residue was purified by silica gel chromatography
using hexanes to Et2O/hexanes (1:100) as eluent to give the product
1
4b (158 mg, 60%). An oil; TLC (Et2O/hexanes (1:5)) Rf = 0.38; H
NMR (300 MHz, CDCl3) δ 3.01 (s, 1 H), 4.14 (d, J = 10.5 Hz, 1 H),
4.16 (d, J = 10.5 Hz, 1 H), 4.98 (d, J = 6.6 Hz, 2 H), 5.81 (t, J = 6.6
Hz, 1 H), 7.24−7.29 (m, 1 H), 7.36 (s, 1 H), 7.81 (d, J = 8.7 Hz, 1 H);
13C NMR (75 MHz, CDCl3) δ 51.2 (CH2), 74.3 (C), 80.2 (CH2),
94.3 (CH), 127.2 (CH), 129.7 (CH), 130.8 (CH), 131.6 (C), 134.4
(C), 137.6 (C), 207.3 (C); IR (neat) 3552, 1956, 1581 cm−1; ESI-MS
m/z (rel intensity) 264 ([M + 2]+, 57), 262 ([M]+, 54), 214 (100),
158 (93); HRMS [M]+ calcd for C11H9OCl3 261.9713, found
261.9722.
4-(1-Bromo-2-hydroxypenta-3,4-dien-2-yl)benzonitrile (4g,
Table 1, entry 7). Following the general procedure, a mixture of
4g and its corresponding methyl ketone 4g″ was obtained. To the
mixture in MeOH (2 mL) was added NaBH4 (25 mg, 0.65 mmol) at
rt, and the resulting mixture was stirred at rt for 2 h. Et2O (15 mL) and
water (3 mL) were added, and the mixture was transferred to a
separatory funnel. The aqueous layer was back extracted with Et2O (15
mL × 2). The combined organic layers were concentrated in a rotary
evaporator. The residue was purified by silica gel chromatography
using hexanes to Et2O/hexanes (1:100) as eluent to give the product
1-Bromo-2-phenylpenta-3,4-dien-2-ol (4c, Table 1, entry 3).
Following the general procedure, the title compound was obtained
1
(148 mg, 62%). An oil; TLC (Et2O/hexanes (1:5)) Rf = 0.38; H
NMR (300 MHz, CDCl3) δ 2.89 (s, 1 H), 3.72 (d, J = 10.2 Hz, 1 H),
3.81 (d, J = 10.2 Hz, 1 H), 5.03 (d, J = 6.9 Hz, 2 H), 5.55 (t, J = 6.9
Hz, 1 H), 7.26−7.40 (m, 3 H), 7.47−7.51 (m, 2 H); 13C NMR (75
MHz, CDCl3) δ 44.3 (CH2), 73.4 (C), 79.9 (CH2), 96.7 (CH), 125.4
(CH × 2), 127.8 (CH), 128.3 (CH × 2), 142.2 (C), 206.6 (C); IR
(neat) 3538, 3067, 1949 cm−1. These data are in agreement with those
reported in the literature.4
1
4g (87 mg, 33%). An oil; TLC (Et2O/hexanes (1:1)) Rf = 0.28; H
NMR (300 MHz, CDCl3) δ 2.92 (s, 1 H), 3.69 (d, J = 10.5 Hz, 1 H),
3.78 (d, J = 10.5 Hz, 1 H), 5.03 (d, J = 6.6 Hz, 2 H), 5.51 (t, J = 6.6
Hz, 1 H), 7.59 (d, J = 8.7 Hz,, 2 H), 7.65 (d, J = 8.7 Hz, 2 H); 13C
NMR (75 MHz, CDCl3) δ 43.2 (CH2), 73.7 (C), 80.4 (CH2), 96.1
(CH), 111.8 (C), 118.5 (C), 126.5 (CH × 2), 132.1 (CH × 2), 147.6
(C), 206.8 (C); IR (neat) 3464, 2235, 1948 cm−1; ESI-MS m/z (rel
intensity) 288 ([M + Na + 2]+, 14), 286 ([M + Na]+, 18), 192 (72),
96 (100); HRMS [M + Na]+ calcd for C12H10ONBrNa 285.9838,
found 285.9824.
1-Bromo-2-(4-chlorophenyl)penta-3,4-dien-2-ol (4d, Table
1, entry 4). Following the general procedure, a mixture of 4d and
its corresponding methyl ketone 4d″ was obtained. To the mixture in
MeOH (2 mL) was added NaBH4 (25 mg, 0.65 mmol) at rt, and the
resulting mixture was stirred at rt for 2 h. Et2O (15 mL) and water (3
mL) were added, and the mixture was transferred to a separatory
funnel. The aqueous layer was back extracted with Et2O (15 mL × 2).
The combined organic layers were concentrated in a rotary evaporator.
The residue was purified by silica gel chromatography using hexanes to
Et2O/hexanes (1:100) as eluent to give the product 4d (140 mg,
1-Bromo-2-(4-methoxyphenyl)penta-3,4-dien-2-ol (4h,
Table 1, entry 8). Following the general procedure, the title
compound was obtained (161 mg, 60%). An oil; TLC (Et2O/hexanes
1
51%). An oil; TLC (Et2O/hexanes (1:5)) Rf = 0.30; H NMR (300
1
(1:5)) Rf = 0.35; H NMR (300 MHz, CDCl3) δ 2.87 (s, 1 H), 3.69
MHz, CDCl3) δ 2.87 (s, 1 H), 3.68 (d, J = 10.5 Hz, 1 H), 3.76 (d, J =
10.5 Hz, 1 H), 5.02 (d, J = 6.6 Hz, 2 H), 5.50 (t, J = 6.6 Hz, 1 H), 7.31
(d, J = 8.7 Hz, 2 H), 7.41 (d, J = 8.7 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 43.9 (CH2), 73.5 (C), 80.1 (CH2), 96.4 (CH), 127.0 (CH ×
2), 128.4 (CH × 2), 133.7 (C), 140.8 (C), 206.6 (C); IR (neat) 3544,
1956, 1488 cm−1; ESI-MS m/z (rel intensity) 274 ([M + 2]+, 28), 272
([M]+, 42), 224 (100), 183 (41); HRMS [M]+ calcd for C11H10OBrCl
271.9598, found 271.9600.
(d, J = 10.5 Hz, 1 H), 3.77 (d, J = 10.5 Hz, 1 H), 3.79 (s, 3 H), 5.01 (d,
J = 6.6 Hz, 2 H), 5.53 (t, J = 6.6 Hz, 1 H), 6.88 (d, J = 6.9 Hz, 2 H),
7.41 (d, J = 6.9 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 44.5 (CH2),
55.2 (CH3), 73.5 (C), 79.8 (CH2), 96.7 (CH), 113.6 (CH × 2), 126.7
(CH × 2), 134.2 (C), 159.1 (C), 206.5 (C); IR (neat) 3557, 1606,
1523 cm−1; ESI-MS m/z (rel intensity) 293 ([M + Na + 2]+, 35), 291
([M + Na]+, 36), 251 (68), 171 (100); HRMS [M + Na]+ calcd for
C12H13O2BrNa 290.9991, found 290.9978.
1-Bromo-2-(2-methoxyphenyl)penta-3,4-dien-2-ol (4i, Table
1, entry 9). Following the general procedure, the title compound was
obtained (178 mg, 66%). An oil; TLC (Et2O/hexanes (1:5)) Rf = 0.33;
1H NMR (300 MHz, CDCl3) δ 3.57 (s, 1 H), 3.86 (s, 3 H), 3.95 (d, J
= 10.2 Hz, 1 H), 4.001 (d, J = 10.2 Hz, 1 H), 4.92−5.04 (m, 2 H), 5.84
(t, J = 6.6 Hz, 1 H), 6.90 (d, J = 7.5 Hz, 1 H), 7.01 (d, J = 7.5 Hz, 1
H), 7.26−7.32 (m, 1 H), 7.60 (d, J = 7.5 Hz, 1 H); 13C NMR (75
MHz, CDCl3) δ 42.4 (CH2), 55.3 (CH3), 73.4 (C), 79.7 (CH2), 95.7
(CH), 111.1 (CH), 120.8 (CH), 127.3 (CH), 129.2 (CH), 129.7 (C),
155.9 (C), 206.5 (C); IR (neat) 3538, 2953, 1477 cm−1; ESI-MS m/z
(rel intensity) 293 ([M + Na + 2]+, 77), 291 ([M + Na]+, 82), 211
(100), 172 (95); HRMS [M + Na]+ calcd for C12H13O2BrNa
290.9991, found 290.9981.
1-Bromo-2-(4-bromophenyl)penta-3,4-dien-2-ol (4e, Table
1, entry 5). Following the general procedure, a mixture of 4e and its
corresponding methyl ketone 4e″ was obtained. To the mixture in
MeOH (2 mL) was added NaBH4 (25 mg, 0.65 mmol) at rt, and the
resulting mixture was stirred at rt for 2 h. Et2O (15 mL) and water (3
mL) were added, and the mixture was transferred to a separatory
funnel. The aqueous layer was back extracted with Et2O (15 mL × 2).
The combined organic layers were concentrated in a rotary evaporator.
The residue was purified by silica gel chromatography using hexanes to
Et2O/hexanes (1:100) as eluent to give the product 4e (118 mg, 37%).
1
An oil; TLC (Et2O/hexanes (1:5)) Rf = 0.30; H NMR (300 MHz,
CDCl3) δ 2.85 (s, 1 H), 3.68 (d, J = 10.5 Hz, 1 H), 3.76 (d, J = 10.5
Hz, 1 H), 5.02 (d, J = 6.6 Hz, 2 H), 5.50 (t, J = 6.6 Hz, 1 H), 7.34 (d, J
= 9.0 Hz, 2 H), 7.46 (d, J = 9.0 Hz, 2 H); 13C NMR (75 MHz, CDCl3)
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Note
2-Methyl-1,4-diphenyl-1H-pyrrole (6a). Following the general
3 H), 6.28 (s, 1 H), 6.92−6.98 (m, 3 H), 7.20−7.25 (m, 2 H), 7.33−
7.43 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 12.7 (CH3), 55.5
(CH3), 105.6 (CH), 114.2 (CH × 2), 118.3 (CH), 118.6 (C), 122.9
(C), 126.4 (CH × 2), 127.0 (CH × 2), 130.7 (C), 131.5 (CH × 2),
132.9 (C), 134.6 (C), 158.6 (C); IR (KBr) 2930, 1680, 1518 cm−1; EI-
MS m/z (rel intensity) 343 ([M + 2]+, 99), 341 ([M]+, 100), 326
(17), 221 (33); HRMS [M]+ calcd for C18H16BrNO 341.0415, found
341.0421.
procedure, the title compound was obtained (113 mg, 81%). Solid, mp
1
68−70 °C; TLC (Et2O/hexanes (1:5)) Rf = 0.63; H NMR (300
MHz, CDCl3) δ 2.24 (s, 3 H), 6.36 (s, 1 H), 7.06 (s, 1 H), 7.13 (t, J =
8.7 Hz, 1 H), 7.29−7.38 (m, 5 H), 7.43 (d, J = 8.7 Hz, 2 H), 7.45 (J =
8.7 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 12.9 (CH3), 106.5 (CH),
117.8 (CH), 124.4 (C), 124.8 (CH × 2), 125.3 (CH), 125.5 (CH ×
2), 126.9 (CH), 128.5 (CH × 2), 129.0 (CH × 2), 130.4 (C), 135.5
(C), 140.3 (C); IR (KBr) 3026, 1602, 1504 cm−1. These data are in
agreement with those reported in the literature.10
2-Methyl-4-phenylthiophene (7c). Following the general
procedure, the title compound was obtained (63 mg, 60%). Solid,
1
mp 74−75 °C; TLC (Et2O/hexanes (1:5)) Rf = 0.75; H NMR (300
1-(4-Methoxyphenyl)-2-methyl-4-phenyl-1H-pyrrole (6b).
Following the general procedure, the title compound was obtained
(122 mg, 77%). Solid, mp 105−106 °C; TLC (Et2O/hexanes (1:5)) Rf
MHz, CDCl3) δ 2.53 (s, 3 H), 7.05 (s, 1 H), 7.19 (s, 1 H), 7.25 (d, J =
8.1 Hz, 1 H), 7.35 (d, J = 8.1 Hz, 2 H), 7.54 (d, J = 8.1 Hz, 2 H); 13C
NMR (75 MHz, CDCl3) δ 15.4 (CH3), 117.9 (CH), 124.5 (CH),
126.1 (CH × 2), 126.8 (CH), 128.6 (CH × 2), 136.0 (C), 140.4 (C),
141.9 (C); IR (KBr) 2917, 1502, 1198 cm−1. These data are in
agreement with those reported in the literature.12
1
= 0.70; H NMR (300 MHz, CDCl3) δ 2.22 (s, 3 H), 3.85 (s, 3 H),
6.37 (s, 1 H), 6.99 (d, J = 8.1 Hz, 2 H), 7.05 (s, 1 H), 7.18 (t, J = 8.1
Hz, 1 H), 7.29 (d, J = 8.1 Hz, 2 H), 7.35 (t, J = 8.1 Hz, 2 H), 7.53 (d, J
= 8.1 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 12.7 (CH3), 55.4
(CH3), 105.8 (CH), 114.1 (CH × 2), 118.1 (CH), 124.0 (C), 124.8
(CH × 2), 125.3 (CH), 126.9 (CH × 2), 128.5 (CH × 2), 130.4 (C),
133.1 (C), 135.6 (C), 158.5 (C); IR (KBr) 2937, 1602, 1504 cm−1; EI-
MS m/z (rel intensity) 263 ([M]+, 100), 248 (30), 207 (14), 115
(11); HRMS [M]+ calcd for C18H17NO 263.1310, found 263.1315.
1-Benzyl-2-methyl-4-phenyl-1H-pyrrole (6c). Following the
general procedure, the title compound was obtained (113 mg, 76%).
4-(4-Chlorophenyl)-2-methylthiophene (7d). Following the
general procedure, the title compound was obtained (100 mg, 80%).
1
Solid, mp 121−122 °C; TLC (Et2O/hexanes (1:5)) Rf = 0.70; H
NMR (300 MHz, CDCl3) δ 2.52 (s, 3 H), 7.00 (s, 1 H), 7.16 (s, 1 H),
7.32 (d, J = 9.0 Hz, 2 H), 7.47 (d, J = 9.0 Hz, 2 H); 13C NMR (75
MHz, CDCl3) δ 15.3 (CH3), 118.2 (CH), 124.3 (CH), 127.3 (CH ×
2), 128.8 (CH × 2), 132.6 (C), 134.5 (C), 140.6 (C), 140.8 (C); IR
(KBr) 2918, 1496, 1199 cm−1; EI-MS m/z (rel intensity) 210 ([M +
2]+, 36), 208 ([M]+, 100), 171 (13), 128 (8); HRMS [M]+ calcd for
C11H9SCl 208.0113, found 208.0121.
1
An oil; TLC (Et2O/hexanes (1:5)) Rf = 0.58; H NMR (300 MHz,
CDCl3) δ 2.16 (s, 3 H), 5.03 (s, 2 H), 6.26 (s, 1 H), 6.93 (s, 1 H),
7.03−7.15 (m, 3 H), 7.22−7.32 (m, 5 H), 7.45 (d, J = 8.1 Hz, 2 H);
13C NMR (75 MHz, CDCl3) δ 12.0 (CH3), 50.4 (CH3), 105.3 (CH),
117.5 (CH), 123.5 (C), 124.7 (CH × 2), 125.0 (CH), 126.3 (CH ×
2), 127.3 (CH), 128.4 (CH × 2), 128.7 (CH × 2), 129.9 (C), 135.8
(C), 138.0 (C); IR (neat) 2921, 1608, 1519 cm−1. These data are in
agreement with those reported in the literature.11
4-(4-Bromophenyl)-2-methylthiophene (7e). Following the
general procedure, the title compound was obtained (111 mg, 73%).
1
Solid, mp 134−135 °C; TLC (Et2O/hexanes (1:5)) Rf = 0.70; H
NMR (300 MHz, CDCl3) δ 2.51 (s, 3 H), 7.00 (s, 1 H), 7.17 (s, 1 H),
7.39 (d, J = 8.1 Hz, 2 H), 7.48 (d, J = 8.1 Hz, 2 H); 13C NMR (75
MHz, CDCl3) δ 15.3 (CH3), 118.3 (CH), 120.7 (C), 124.2 (CH),
127.6 (CH × 2), 131.7 (CH × 2), 134.9 (C), 140.6 (C), 140.8 (C); IR
(KBr) 2923, 1508, 1191 cm−1; EI-MS m/z (rel intensity) 254 ([M +
2]+, 100), 252 ([M]+, 98), 228 (9), 171 (28); HRMS [M]+ calcd for
C11H9BrS 251.9608, found 251.9611.
4-(4-Chlorophenyl)-2-methyl-1-phenyl-1H-pyrrole (6d). Fol-
lowing the general procedure, the title compound was obtained (127
mg, 79%). Solid, mp 106−107 °C; TLC (Et2O/hexanes (1:5)) Rf =
0.63; 1H NMR (300 MHz, CDCl3) δ 2.24 (s, 3 H), 6.34 (s, 1 H), 7.05
(s, 1 H), 7.28−7.49 (m, 9 H); 13C NMR (75 MHz, CDCl3) δ 12.9
(CH3), 106.3 (CH), 118.0 (CH), 123.3 (C), 125.6 (CH × 2), 126.0
(CH × 2), 127.1 (CH), 128.6 (CH × 2), 129.1 (CH × 2), 130.4 (C),
130.8 (C), 134.0 (C), 139.9 (C); IR (KBr) 2960, 1523, 1161 cm−1; EI-
MS m/z (rel intensity) 269 ([M + 2]+, 33), 267 ([M]+, 100), 228 (5),
191 (20); HRMS [M]+ calcd for C17H14ClN 267.0815, found
267.0818.
4-(4-Chlorophenyl)-1-(4-methoxyphenyl)-2-methyl-1H-pyr-
role (6e). Following the general procedure, the title compound was
obtained (157 mg, 88%). Solid, mp 108−109 °C; TLC (Et2O/hexanes
(1:5)) Rf = 0.50; 1H NMR (300 MHz, CDCl3) δ 2.17 (s, 3 H), 3.84 (s,
3 H), 6.28 (s, 1 H), 6.93−6.98 (m, 3 H), 7.20−7.28 (m, 4 H), 7.42 (d,
J = 8.7 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 12.7 (CH3), 55.5
(CH3), 105.7 (CH), 114.2 (CH × 2), 118.2 (CH), 122.9 (C), 126.0
(CH × 2), 126.9 (CH × 2), 128.6 (CH × 2), 130.6 (C), 130.7 (C),
132.9 (C), 134.2 (C), 158.6 (C); IR (KBr) 2919, 1514, 1245 cm−1; EI-
MS m/z (rel intensity) 299 ([M + 2]+, 33), 297 ([M]+, 100), 282
(24), 221 (26); HRMS [M]+ calcd for C18H16ClNO 297.0920, found
297.0914.
4-(4-Bromophenyl)-2-methyl-1-phenyl-1H-pyrrole (6f). Fol-
lowing the general procedure, the title compound was obtained (170
mg, 91%). Solid, mp 106−107 °C; TLC (Et2O/hexanes (1:5)) Rf =
0.55; 1H NMR (300 MHz, CDCl3) δ 2.24 (s, 3 H), 6.35 (s, 1 H), 7.06
(s, 1 H), 7.24−7.49 (m, 9 H); 13C NMR (75 MHz, CDCl3) δ 12.9
(CH3), 106.3 (CH), 118.0 (CH), 118.7 (C), 123.2 (C), 125.5 (CH ×
2), 126.4 (CH × 2), 127.1 (CH), 129.1 (CH × 2), 130.4 (C), 131.5
(CH × 2), 134.5 (C), 139.8 (C); IR (KBr) 2960, 1601, 1495 cm−1; EI-
MS m/z (rel intensity) 313 ([M + 2]+, 100), 311 ([M]+, 99), 230
(14), 191 (27); HRMS [M]+ calcd for C17H14BrN 311.0310, found
311.0304.
2-Methyl-4-(p-tolyl)thiophene (7f, Table 2, entry 1). Follow-
ing the general procedure, the title compound was obtained (90 mg,
32%). Solid, mp 107−108 °C; TLC (Et2O/hexanes (1:5)) Rf = 0.73;
1H NMR (300 MHz, CDCl3) δ 2.35 (s, 3 H), 2.51 (s, 3 H), 7.03 (s, 1
H),7.15 (d, J = 8.1 Hz, 2 H), 7.19 (s, 1 H), 7.45 (d, J = 8.1 Hz, 2 H);
13C NMR (75 MHz, CDCl3) δ 15.3 (CH3), 21.0 (CH3), 117.3 (CH),
124.5 (CH), 126.0 (CH × 2), 129.3 (CH × 2), 133.2 (C), 136.5 (C),
140.2 (C), 141.9 (C). These data are in agreement with those reported
in the literature.13
4-(5-Methylthiophen-3-yl)benzonitrile (7g, Table 2, entry 2).
Following the general procedure, the title compound was obtained
(132 mg, 44%). Solid, mp 109−110 °C; TLC (Et2O/hexanes (1:1)) Rf
1
= 0.65; H NMR (300 MHz, CDCl3) δ 2.51 (s, 3 H), 7.03 (s, 1 H),
7.29 (s, 1 H), 7.57 (d, J = 9.0 Hz, 2 H), 7.62 (d, J = 9.0 Hz, 2 H); 13C
NMR (75 MHz, CDCl3) δ 15.3 (CH3), 110.0 (C), 118.9 (C), 120.3
(CH), 123.9 (CH), 126.4 (CH × 2), 132.5 (CH × 2), 139.8 (C),
140.0 (C), 141.4 (C); IR (KBr) 2920, 2232, 1604 cm−1; EI-MS m/z
(rel intensity) 199 ([M]+, 100), 198 (77), 166 (8), 154 (9); HRMS
[M]+ calcd for C12H9NS 199.0456, found 199.0454.
4-(4-Methoxyphenyl)-2-methylthiophene (7h, Table 2, entry
3). Following the general procedure, the title compound was obtained
(67 mg, 22%). Solid, mp 110−111 °C; TLC (Et2O/hexanes (1:5)) Rf
1
= 0.60; H NMR (300 MHz, CDCl3) δ 2.50 (s, 3 H), 3.81 (s, 3 H),
6.89 (d, J = 9.0 Hz, 2 H), 6.99 (s, 1 H), 7.06 (s, 1 H), 7.46 (d, J = 9.0
Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 15.3 (CH3), 55.3 (CH3),
114.1 (CH × 2), 116.6 (CH), 124.5 (CH), 127.3 (CH × 2), 129.0
(C), 140.3 (C), 141.7 (C), 158.7 (C); IR (KBr) 2919, 1532, 1255
cm−1; EI-MS m/z (rel intensity) 204 ([M]+, 100), 189 (74), 161 (25),
115 (6); HRMS [M]+ calcd for C12H12OS 204.0609, found 204.0600.
4-(2,5-Dimethoxyphenyl)-2-methylthiophene (7j, Table 2,
entry 4). Following the general procedure, the title compound was
obtained (105 mg, 30%). An oil; TLC (Et2O/hexanes (1:5)) Rf = 0.50;
1H NMR (300 MHz, CDCl3) δ 2.51 (s, 3 H), 3.79 (s, 3 H), 3.80 (s, 3
4-(4-Bromophenyl)-1-(4-methoxyphenyl)-2-methyl-1H-pyr-
role (6g). Following the general procedure, the title compound was
obtained (193 mg, 94%). Solid, mp 98−99 °C; TLC (Et2O/hexanes
(1:5)) Rf = 0.45; 1H NMR (300 MHz, CDCl3) δ 2.17 (s, 3 H), 3.84 (s,
2756
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The Journal of Organic Chemistry
Note
H), 6.78 (dd, J = 9.0, 3.0 Hz, 1 H), 6.88 (d, J = 9.0 Hz, 1 H), 7.02 (d, J
= 3.0 Hz, 1 H), 7.08 (s, 1 H), 7.34 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 15.3 (CH3), 55.7 (CH3), 56.1 (CH3), 112.4 (CH), 112.5
(CH), 115.4 (CH), 121.2 (CH), 126.2 (C), 126.6 (CH), 137.8 (C),
138.7 (C), 150.7 (C), 153.5 (C); IR (neat) 2956, 1690, 1496 cm−1;
EI-MS m/z (rel intensity) 234 ([M]+, 100), 219 (59), 204 (12), 191
(17); HRMS [M]+ calcd for C13H14SO2 234.0715, found 234.0713.
2-Methyl-4-(naphthalen-2-yl)thiophene (7k, Table 2, entry
5). Following the general procedure, the title compound was obtained
(74 mg, 22%). Solid, mp 114−116 °C; TLC (Et2O/hexanes (1:5)) Rf
= 0.63; 1H NMR (300 MHz, CDCl3) δ 2.55 (s, 3 H), 7.18−7.20 (m, 1
H), 7.30 (d, J = 1.8 Hz, 1 H), 7.40−7.49 (m, 2 H), 7.70 (dd, J = 8.4,
1.8 Hz, 1 H), 7.79−7.85 (m, 3 H), 7.95 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 15.4 (CH3), 118.4 (CH), 124.4 (CH), 124.7 (CH), 124.8
(CH), 125.6 (CH), 126.2 (CH), 127.6 (CH), 127.9 (CH), 128.3
(CH), 132.5 (C), 133.4 (C), 133.7 (C), 140.6 (C), 141.9 (C); IR
(KBr) 3048, 1600, 1217 cm−1; EI-MS m/z (rel intensity) 224 ([M]+,
100), 223 (25), 178 (8), 112 (7); HRMS [M]+ calcd for C15H12S
224.0660, found 224.0654.
+ 2]+, 100), 236 ([M]+, 99), 207 (17), 128 (85); HRMS [M]+ calcd
for C11H9BrO 235.9837, found 235.9841.
ASSOCIATED CONTENT
* Supporting Information
■
S
X-ray crystallographic data (1b, 1g) and complete character-
ization data (1H and 13C{1H} NMR data) for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: mhlin@cc.ncue.edu.tw.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
2-Methyl-4-(4-(methylsulfonyl)phenyl)thiophene (7l, Table
2, entry 6). Following the general procedure, the title compound was
obtained (136 mg, 36%). Solid, mp 140−141 °C; TLC (EtOAc/
Financial support from the National Science Council of the
Republic of China, Taiwan (NSC102-2113-M-018-004-MY2) is
gratefully acknowledged. We also thank the assistance from
Professor Jui-Hsien Huang’s group for the X-ray structure
determination.
1
hexanes (1:1)) Rf = 0.70; H NMR (300 MHz, CDCl3) δ 2.52 (s, 3
H), 3.05 (s, 3 H), 7.06 (s, 1 H), 7.33 (s, 1 H), 7.70 (d, J = 8.7 Hz, 2
H), 7.91 (d, J = 8.7 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 15.2
(CH3), 44.4 (CH3), 120.5 (CH), 124.0 (CH), 126.6 (CH × 2), 127.8
(CH × 2), 138.1 (C), 139.6 (C), 141.0 (C), 141.3 (C); IR (KBr)
3011, 2928, 1599 cm−1; EI-MS m/z (rel intensity) 252 ([M]+, 28),
201 (11), 173 (15), 130 (100); HRMS [M]+ calcd for C12H12O2S2
252.0279, found 252.0275.
REFERENCES
■
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4-(3-Bromophenyl)-2-methylthiophene (7m, Table 2, entry
7). Following the general procedure, the title compound was obtained
(175 mg, 46%). Solid, mp 45−47 °C; TLC (Et2O/hexanes (1:5)) Rf =
(2) (a) Rodebaugh, R. M.; Cromwell, N. H. Tetrahedron Lett. 1967,
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(g) Potikha, L. M.; Kovtunenko, V. A.; Turov, A. V. Chem. Heterocycl.
Compd. 2009, 45, 815. (h) Potikha, L. M.; Kovtunenko, V. A.; Turov,
A. V.; Palamarchuk, G. V.; Zubatyuk, R. I.; Shishkin, O. V. Chem.
Heterocycl. Compd. 2009, 45, 327. (i) Potikha, L. M.; Kovtunenko, V.
A. Chem. Heterocycl. Compd. 2006, 42, 741.
(3) Ma, S.; Wang, G. Tetrahedron Lett. 2002, 43, 5723.
(4) Fandrick, D. R.; Saha, J.; Fandrick, K. R.; Sanyal, S.; Ogikubo, J.;
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1
0.75; H NMR (300 MHz, CDCl3) δ 2.51 (s, 3 H), 7.00 (s, 1 H),
7.18−7.24 (m, 2 H), 7.39 (d, J = 8.7 Hz, 1 H), 7.45 (d, J = 8.7 Hz, 1
H), 7.69 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 15.3 (CH3), 118.8
(CH), 122.8 (C), 124.3 (CH), 124.7 (CH), 129.2 (CH), 129.7 (CH),
130.1 (CH), 138.1 (C), 140.4 (C), 140.8 (C); IR (KBr) 3113, 1570,
1070 cm−1; EI-MS m/z (rel intensity) 254 ([M + 2]+, 100), 252
([M]+, 97), 171 (24), 129 (18); HRMS [M]+ calcd for C11H9BrS
251.9608, found 251.9605.
2-Methyl-4-phenylfuran (8c). Following the general procedure,
the title compound was obtained (43 mg, 45%). Solid, mp 67−68 °C;
TLC (EtOAc/hexanes (1:4)) Rf = 0.70; 1H NMR (300 MHz, CDCl3)
δ 2.37 (s, 3 H), 6.35 (s, 1 H), 7.25−7.31 (m, 1 H), 7.41 (t, J = 8.1 Hz,
2 H), 7.50 (d, J = 8.1 Hz, 2 H), 7.63 (s, 1 H); 13C NMR (75 MHz,
CDCl3) δ 13.5 (CH3), 104.8 (CH), 125.6 (CH × 2), 126.6 (CH),
127.1 (C), 128.6 (CH × 2), 132.7 (C), 136.5 (CH), 153.1 (C); IR
(KBr) 2929, 1558, 1122 cm−1. These data are in agreement with those
reported in the literature.14
4-(4-Chlorophenyl)-2-methylfuran (8d). Following the general
(6) Lin, M.-H.; Kuo, C.-K.; Lin, W.-C.; Huang, Y.-C.; Tsai, Y.-T.;
Liang, K.-Y.; Li, Y.-S.; Chuang, T.-H. Tetrahedron 2013, 69, 8263.
procedure, the title compound was obtained (55 mg, 48%). Solid, mp
1
91−92 °C; TLC (EtOAc/hexanes (1:4)) Rf = 0.70; H NMR (300
(7) Cordier, P.; Aubert, C.; Malacria, M.; Laco
Angew. Chem., Int. Ed. 2009, 48, 8757.
̂
te, E.; Gandon, V.
MHz, CDCl3) δ 2.31 (s, 3 H), 6.24 (s, 1 H), 7.29 (d, J = 8.0 Hz, 2 H),
7.34 (d, J = 8.0 Hz, 2 H), 7.54 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ
13.5 (CH3), 104.6 (CH), 126.1 (C), 126.8 (CH × 2), 128.8 (CH ×
2), 131.3 (C), 132.2 (C), 136.7 (CH), 153.4 (C); IR (KBr) 2919,
1553, 1137 cm−1; EI-MS m/z (rel intensity) 194 ([M + 2]+, 33), 192
([M]+, 100), 163 (24), 128 (53); HRMS [M]+ calcd for C11H9ClO
192.0342, found 192.0346.
(8) Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Tiekink, E. R. T. J.
Org. Chem. 2003, 68, 4239.
(9) The structures have been deposited with the Cambridge
Crystallographic Data Centre (1b: CCDC 978053, 1g: CCDC
978502). These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
4-(4-Bromophenyl)-2-methylfuran (8e). Following the general
procedure, the title compound was obtained (65 mg, 46%). Solid, mp
(10) Kim, S. H.; Lim, J. W.; Lim, C. H.; Kim, J. N. Bull. Korean Chem.
Soc. 2012, 33, 620.
1
109−110 °C; TLC (EtOAc/hexanes (1:4)) Rf = 0.68; H NMR (300
MHz, CDCl3) δ 2.32 (s, 3 H), 6.24 (s, 1 H), 7.29 (d, J = 8.0 Hz, 2 H),
7.45 (d, J = 8.0 Hz, 2 H), 7.56 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ
13.5 (CH3), 104.5 (CH), 120.3 (C), 126.1 (C), 127.1 (CH × 2),
131.7 (CH × 2), 131.7 (C), 136.7 (CH), 153.5 (C); 13C NMR (75
MHz, acetone-d6) δ 13.4 (CH3), 105.2 (CH), 120.5 (C), 126.8 (C),
128.1 (CH × 2), 132.5 (CH × 2), 132.9 (C), 138.3 (CH), 154.2 (C);
IR (KBr) 2922, 1553, 1410 cm−1; EI-MS m/z (rel intensity) 238 ([M
(11) Kiren, S.; Hong, X.; Leverett, C. A.; Padwa, A. Org. Lett. 2009,
11, 1233.
(12) Kashulin, I. A.; Nifant’ev, I. E. J. Org. Chem. 2004, 69, 5479.
(13) Funaki, K.; Sato, T.; Qi, S. Org. Lett. 2012, 14, 6186.
(14) Okazaki, R.; Negishi, Y.; Inamoto, N. J. Org. Chem. 1984, 49,
3819.
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dx.doi.org/10.1021/jo5001274 | J. Org. Chem. 2014, 79, 2751−2757